Azole Antifungals

Azole antifungals inhibit fungal cytochrome P450 14-alpha-demethylase, blocking ergosterol synthesis. They are divided into imidazoles (ketoconazole, clotrimazole, miconazole) and triazoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole). Triazoles are the backbone of therapy for candidiasis, cryptococcosis, aspergillosis and endemic mycoses, but they inhibit human CYP3A4, causing extensive interactions.

Pharmacokinetics. Fluconazole is highly bioavailable, water soluble, widely distributed including cerebrospinal fluid, and excreted unchanged by the kidney. Itraconazole, voriconazole, posaconazole and isavuconazole are lipophilic and hepatically metabolised, and are not excreted unchanged in urine.

• Fluconazole: yeasts, Cryptococcus, Coccidioides; no activity against Aspergillus or Candida krusei; variable against Candida glabrata.
• Itraconazole: dimorphic fungi, sporotrichosis, chromoblastomycosis, eumycetoma, dermatophytes, Aspergillus. Capsules need food and gastric acid; oral solution is taken without food. Negative inotrope; avoid in heart failure.
• Voriconazole: first-line for invasive aspergillosis. Nonlinear kinetics, CYP2C19 polymorphism changes exposure, visual disturbance, hallucinations, photosensitivity.
• Posaconazole: broad activity including mucormycosis; used for prophylaxis in high-risk haematological patients.
• Isavuconazole: aspergillosis and mucormycosis; shortens QT interval; fewer visual and hepatic effects.
• Ketoconazole: oral use restricted because of fatal hepatotoxicity and adrenal suppression.

Fluconazole (adult).

• Vaginal candidiasis: 150 mg single dose.
• Oropharyngeal candidiasis: 100 to 200 mg daily for 7 to 14 days. Oesophageal: 200 to 400 mg daily for 14 to 21 days.
• Candidaemia step-down: 800 mg loading then 400 mg daily.
• Cryptococcal meningitis: 1200 mg daily with induction, then 800 mg daily for 8 weeks, then 200 mg daily maintenance.
• Children: 6 to 12 mg/kg daily, maximum 400 mg.

Itraconazole. 200 mg three times daily for 3 days, then 200 mg once or twice daily. Treatment of histoplasmosis continues 6 to 12 months. Treatment trough over 1 mg/L (itraconazole plus hydroxy-itraconazole).

Voriconazole. 6 mg/kg intravenously every 12 hours for 2 doses, then 4 mg/kg every 12 hours; oral 400 mg every 12 hours for 2 doses, then 200 mg every 12 hours for adults over 40 kg. Trough 1 to 5.5 mg/L. Halve maintenance in mild to moderate cirrhosis.

Posaconazole. Delayed-release tablets 300 mg twice daily on day 1, then 300 mg daily with food; prophylaxis trough over 0.7 mg/L, treatment over 1 mg/L.

Isavuconazole. 200 mg isavuconazole (372 mg isavuconazonium sulphate) every 8 hours for 6 doses, then 200 mg daily.

Contraindications. Co-administration with QT-prolonging drugs (pimozide, quinidine, cisapride), simvastatin and lovastatin, ergot alkaloids, and (for voriconazole) rifampicin, rifabutin, carbamazepine and long-acting barbiturates. Isavuconazole is contraindicated in familial short QT.

Serious adverse effects. Hepatotoxicity, QT prolongation and torsades, adrenal suppression (ketoconazole), heart failure (itraconazole), skin cancer with long-term voriconazole, periostitis and fluorosis, pseudo-hyperaldosteronism with posaconazole.

Major interactions. Increased levels of ciclosporin, tacrolimus, sirolimus, warfarin, vincristine, midazolam, many direct oral anticoagulants, and statins. Rifampicin and phenytoin reduce azole levels and can cause treatment failure.

Monitoring. Liver enzymes at baseline, again within 2 to 4 weeks, and periodically during longer courses. ECG and electrolytes in QT risk. Voriconazole and itraconazole levels at day 5 to 7. Visual symptoms with voriconazole.

Special groups.

• Pregnancy: avoid; high-dose fluconazole is teratogenic in the first trimester. Breastfeeding: fluconazole acceptable at usual doses.
• Kidney impairment: halve fluconazole maintenance when creatinine clearance is under 50 mL/min; avoid the intravenous cyclodextrin-based forms of itraconazole and voriconazole when it is under 50 mL/min unless essential.
• Liver impairment: reduce voriconazole; avoid itraconazole in active liver disease.
• Children: voriconazole needs higher weight-based doses and level monitoring.